Substance P (SP) is one of the most abundant peptides in the central nervous system and has been implicated in a variety of physiological and pathophysiological processes including stress regulation, as well as affective and anxiety-related behaviour. Consistent with these functions, SP and its preferred neurokinin 1 (NK1) receptor has been found within brain areas known to be involved in the regulation of stress and anxiety responses. Aversive and stressful stimuli have been shown repeatedly to change SP brain tissue content, as well as NK1 receptor binding. More recently it has been demonstrated that emotional stressors increase SP efflux in specific limbic structures such as amygdala and septum and that the magnitude of this effect depends on the severity of the stressor. Depending on the brain area, an increase in intracerebral SP concentration (mimicked by SP microinjection) produces mainly anxiogenic-like responses in various behavioural tasks. Based on findings that SP transmission is stimulated under stressful or anxiety-provoking situations it was hypothesised that blockade of NK1 receptors may attenuate stress responses and exert anxiolytic-like effects. Preclinical and clinical studies have found evidence in favour of such an assumption. The status of this research is reviewed here.

Increasing evidence implicates the substance P (SP)͞neurokinin-1 receptor system in anxiety and depression. However, it is not known whether emotional stimulation alters endogenous extracellular SP levels in brain areas important for processing of anxiety and mood, a prerequisite for a contribution of this neuropeptide system in modulating these behaviors. Therefore, we examined in rats whether the release of SP is sensitive to emotional stressors in distinct subregions of the amygdala, a key area in processing of emotions. By using in vivo micropush-pull superfusion and microdialysis techniques, we found a pronounced and long-lasting increase (150%) in SP release in the medial nucleus of the amygdala (MeA), but not in the central nucleus of the amygdala, in response to immobilization stress. SP release in the MeA was transiently enhanced (40%) in response to elevated platform exposure, which is regarded as a mild emotional stressor. T he neuropeptide substance P (SP) and its preferred neurokinin-1 (NK 1 ) receptor have been proposed as possible targets for new antidepressant and anxiolytic therapies. Several preclinical studies have demonstrated a range of anxiety-related behaviors and defensive cardiovascular changes in response to central administration of SP agonists (1-6). Conversely, NK 1 receptor antagonists have been shown to produce anxiolytic-like effects after intracerebroventricular (4) or systemic administration (5,7,8). In addition, mice with selective deletion of the gene encoding the NK 1 receptor or the peptide itself also showed decreased anxiety-related behaviors (9-11). Thus, these findings suggest that SP acting as neurotransmitter͞neuromodulator (for review, see ref. 12) may be of relevance in the regulation of emotional states including anxiety-related behavior. Confirmation of this proposal was obtained by using a highly selective NK 1 receptor antagonist MK-0869, which relieved the symptoms of depression and anxiety in patients with major depressive disorder and a significant degree of anxiety (5). Although it has been shown that emotional and physical stressors modulate SP tissue levels or SP immunoreactivity in brain areas that are implicated in fear and anxiety (13-17), a change in extracellular SP levels, which is a direct and dynamic marker of SP neurotransmission, cannot be reliably predicted from these studies. Hence, at present it is not clear whether emotional stimuli actually do alter the in vivo release of SP, which is a prerequisite for a contribution of this neuropeptide system in modulating emotional states. Since stressful life experiences are thought to play a role in precipitating episodes of neuropsychiatric disorders including anxiety and depression (18,19), and laboratory stressors can produce behavioral and physiological changes resembling these mental disorders (20), it is of particular interest to examine the effect of emotional stressors on SP neurotransmission.The amygdala is critical for the processing of emotions including fear and anxiety (21, 22), and SP-cont...

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To model aspects of trait anxiety/depression, Wistar rats were bred for extremes in either hyper (HAB)-or hypo(LAB)-anxiety as measured on the elevated plus-maze and in a variety of additional behavioral tests. Similar to psychiatric patients, HAB rats prefer passive stress-coping strategies, indicative of depression-like behavior, show hyper-reactivity of the hypothalamo-pituitary-adrenal axis, and a pathological response to the dexamethasone/corticotropin-releasing hormone (CRH) challenge test. Here we tested central mRNA expression, release patterns, and receptor binding of neuropeptides critically involved in the regulation of both anxiety-related behavior and the HPA axis. Thus, CRH, arginine-8-vasopressin (AVP), and oxytocin (OXT) were studied in brains of HAB and LAB males both under basal conditions and after exposure to a mild emotional stressor. In HAB rats, CRH mRNA was decreased in the bed nucleus of the stria terminalis only. While no significant difference in CRH1-receptor binding was found in any brain area, CRH2-receptor binding was elevated in the hypothalamic paraventricular nucleus (PVN), the ventromedial hypothalamus, and the central amygdala of HABs compared to LABs. AVP, but not OXT, mRNA expression as well as release of the neuropeptide, were higher in the PVN of HABs, whereas AVP V1a-receptor binding failed to show significant differences in any brain region studied. Remarkably, intra-PVN treatment of HABs with the AVP V1-receptor antagonist d (CH 2 ) 5 Tyr (Me) AVP resulted in a decrease in anxiety/depression-related behavior. The elevated expression and release of AVP within the PVN of HAB rats together with the behavioral effects of the AVP V1-receptor antagonist suggest a critical involvement of this neuropeptide in neuroendocrine and behavioral phenomena associated with trait anxiety/ depression.